PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) is a highly prevalent disorder with numerous deleterious effects on neurocognitive function and cardiovascular health. However, the leading treatment, continuous positive airway pressure (CPAP), is poorly tolerated by many individuals. Thus, the development new treatment strategies are critically needed. A pharmacological therapy for OSA remains elusive. A key contributor to OSA is reduced pharyngeal dilator muscle tone and responsiveness during sleep. Animal studies support the view that two mechanisms are responsible: a loss of noradrenergic drive and muscarinic inhibition to the hypoglossal motor pool. Accordingly, in a small study in human patients with OSA, we administered a novel combination of existing agents?a noradrenergic reuptake inhibitor atomoxetine plus an antimuscarinic oxybutynin?on a single night, and found a reduction in OSA severity by ~75%, by far the most powerful effect of any pharmacological intervention observed previously. Our current proposal leverages our preliminary findings to make major headway on pharmacological therapy for OSA. In Aim 1, we seek to demonstrate the repeated-dose efficacy and tolerance of atomoxetine-plus-oxybutynin in a randomized, placebo-controlled, crossover study in 48 male and female patients with OSA for 1 month. We will assess effects on OSA severity (apnea-hypopnea index, primary outcome), nocturnal oxygenation, the frequency of arousals from sleep, sleepiness and disease-specific quality of life. Adherence to therapy and adverse events will also be carefully monitored. In Aim 2, we will investigate the mechanisms by which atomoxetine and oxybutynin improve OSA severity, alone and in combination. Using gold-standard ?deep phenotyping? mechanistic studies, we will test the hypotheses that both agents increase muscle responsiveness, separately and synergistically, and that oxybutynin counterbalances the effect of atomoxetine to increase arousability. These results will have key implications for the ongoing development of this pharmacological approach. In Aim 3, we will use both deep phenotyping and non-invasive (clinically-applicable) methods to determine which patient phenotypes respond best to atomoxetine and oxybutynin. Preliminary data strongly suggested that patients with less-severe collapsibility exhibit a greater response to therapy, and that this can be detected with a surrogate measurement from a routine clinical sleep study. This personalized medicine approach will provide the scientific knowledge needed to progress towards larger studies in selected patients. Overall, our proposal is expected to demonstrate that a combination of agents has the potential to treat OSA through reinstatement of muscle responsiveness during sleep. If judiciously administered, this intervention could provide many patients with an effective alternative to CPAP. Such results are of major importance because they have great potential to improve the quality of life and health outcomes of untreated patients with OSA.